PROJECT SUMMARY Traumatic brain injury (TBI) is a devastating medical condition that affects more than 1.7 million civilians in the US and represents an unmet clinical need. Effective therapies are urgently needed, as TBI is associated with high rates of hospitalization, mortality, and disability. Previous clinical trials have failed to demonstrate therapeutic efficacy in patients with TBI. Due to the complex nature of the pathophysiological events accompanying TBI, an effective treatment necessitates the use of drugs with complementary therapeutic effects directed against multiple pathological mechanisms. We have developed a new cyclic peptide-based drug?CN2097?that possesses such properties. When administered peripherally, CN2097 crosses the blood-brain barrier to selectively target PSD-95, an intracellular scaffolding protein required for synapse strengthening (long term potentiation, LTP). CN2097 acts to potentiate brain-derived neurotrophic factor (BDNF) signaling pathways required for neuroprotection and learning. CN2097 produces a prolonged activation of the enzymes involved in memory processes to lower the threshold for LTP, making this compound suited to treat the memory and executive functioning deficits in TBI patients. In addition, CN2097 interferes with glutamate-mediated excitotoxic cell death and is the first in this class of compounds to have anti-neuroinflammatory properties. This suggests that CN2097, by simultaneously redu- cing excitotoxic damage and neuroinflammation, and facilitating synaptic plasticity, is a new multifunctional drug with a significant therapeutic potential to curtail neuronal death and facilitate functional recovery after TBI. There are three major goals of this project that focus on translational (preclinical), mechanistic, and neuro- behavioral aspects of post-traumatic treatment with CN2097. In Aim 1, we will assess the efficacy of CN2097 in mitigating secondary injury and reducing the loss of neural tissue resulting from TBI. The experiments will also be conducted to establish the potential therapeutic time-window for delayed treatment with CN2097, and to quantitatively assess the ability of CN2097 to cross the BBB and determine its distribution in the injured brain. In Aim 2, we will assess the efficacy and mechanism by which CN2097 attenuates synaptic and neuronal loss in the hippocampus and restores synaptic plasticity after TBI. Lastly (Aim 3), we will assess the efficacy of CN2097 in improving neurobehavioral outcome. The multifunctionality of CN2097 together with our initial preclinical data obtained in a rodent model of TBI strongly suggest that this new drug will be highly efficacious in targeting complex secondary injury processes resulting from neurotrauma.